371 – Sex Differences in Cytokine Responses and Genetic Regulation Thereof in People Living With HIV

Background

Females living with HIV have improved viral control but increased immune activation compared to males. Some of these differences appear before puberty, suggesting a role of genetics, but this remains poorly understood. In this study, we assessed the effect of biological sex on circulating cytokine levels and cytokine production upon PBMC stimulation, and the genetic regulation of the latter.

Methods

The 2000HIV study (NTC03994835) included 1895 virally suppressed PLHIV, split into a discovery (1309 males, 233 females) and validation cohort (281 males, 52 females). Plasma levels of 54 cytokines were measured using Olink technology. PBMCs were stimulated with a range of stimuli to assess cytokine production across 77 cytokine-stimuli pairs. Associations with sex were assessed using (rank-based) linear regression. We investigated sex-specific genetic regulation of cytokine responses through sex-stratified cytokine QTL (cytQTL) mapping in individuals from European ancestry (discovery: 861M & 97F, validation: 221M & 26F). Suggestive cytQTLs were tested for sex-specific effects using a student’s t-test, and sex-specific QTLs (ssQTLs) were tested for association with other phenotypic traits using the OpenTargets database.

Results

Females showed significantly (FDR_dis < 0.05 & P_val < 0.05) higher plasma levels of GM-CSF, G-CSF, and CCL22 and significantly lower levels of IL-18, IL-17C, CCL4, IL-16 and IL-22. Cytokine production upon PBMC stimulation was similar between sexes, except for significantly (FDR_dis < 0.05 & P_val < 0.05) increased IL-22 production upon stimulation with S. pneumoniae in females. cytQTL mapping identified 40 independent suggestive (P_dis < 1E-5 & P_val < 0.05) cytQTLs in males and 20 in females, of which 22 were sex specific (P < 8.3E-4). Notably, we identified two SNPs regulating IL-22 responses to C. albicans conidia and E. coli, in females but not in males. Finally, we found that ssQTLs are linked with phenotypic traits related to autoimmune diseases, blood cell composition, and sex hormone levels.

Conclusions

In our study, the effect of sex seems more pronounced on plasma cytokine levels compared to cytokine production upon PBMC stimulation. Yet, sex differences in HIV immunopathogenesis may be driven by differences in cytokine signalling, such as IL-22, which regulates host defences at mucosal sites. We showed sex-specific genetic regulation of cytokine responses in PLHIV, which could be used to stratify PLHIV in immunological intervention studies.

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